Senescence Induction by Combined Ionizing Radiation and DNA Damage Response Inhibitors in Head and Neck Squamous Cell Carcinoma Cells.
Apoptosis
/ drug effects
Ataxia Telangiectasia Mutated Proteins
/ antagonists & inhibitors
Cell Cycle
/ drug effects
Cell Line, Tumor
Cellular Senescence
/ drug effects
DNA Damage
/ drug effects
Fibroblasts
/ drug effects
Head and Neck Neoplasms
/ metabolism
Humans
Isoxazoles
/ pharmacology
Male
Protein Kinase Inhibitors
/ pharmacology
Pyrazines
/ pharmacology
Pyridines
/ pharmacology
Quinolines
/ pharmacology
Radiation, Ionizing
Signal Transduction
/ drug effects
Squamous Cell Carcinoma of Head and Neck
/ metabolism
TOR Serine-Threonine Kinases
/ antagonists & inhibitors
Triazoles
/ pharmacology
ATM
ATR
DNA damage response inhibitor
DNAPK
HNSCC
homologous recombination
ionizing radiation
kinase inhibitor
radiosensitivity
senescence
Journal
Cells
ISSN: 2073-4409
Titre abrégé: Cells
Pays: Switzerland
ID NLM: 101600052
Informations de publication
Date de publication:
01 09 2020
01 09 2020
Historique:
received:
02
06
2020
revised:
28
08
2020
accepted:
30
08
2020
entrez:
5
9
2020
pubmed:
5
9
2020
medline:
15
4
2021
Statut:
epublish
Résumé
DNA damage response inhibitors (DDRi) may selectively enhance the inactivation of tumor cells in combination with ionizing radiation (IR). The induction of senescence may be the key mechanism of tumor cell inactivation in this combinatorial treatment. In the current study the effect of combined IR with DDRi on the induction of senescence was studied in head and neck squamous cell carcinoma (HNSCC) cells with different human papilloma virus (HPV) status. The integrity of homologous recombination (HR) was assessed in two HPV positive, two HPV negative HNSCC, and two healthy fibroblast cell cultures. Cells were treated with the DDRi CC-115 (DNA-dependent protein kinase, DNA-pK; dual mammalian target of rapamycin, mTor), VE-822 (ATR; ataxia telangiectasia and Rad3-related kinase), and AZD0156 (ATM; ataxia telangiectasia mutated kinase) combined with IR. Effects on senescence, apoptosis, necrosis, and cell cycle were analyzed by flow cytometry. The fibroblast cell lines generally tolerated IR or combined treatment better than the tumor cell lines. The ATM and ATR inhibitors were effectively inducing senescence when combined with IR. The DNA-PK inhibitor was not an important inductor of senescence. HPV status and HR activity had a limited influence on the efficacy of DDRi. Induction of senescence and necrosis varied individually among the cell lines due to molecular heterogeneity and the involvement of DNA damage response pathways in senescence induction.
Identifiants
pubmed: 32883016
pii: cells9092012
doi: 10.3390/cells9092012
pmc: PMC7563880
pii:
doi:
Substances chimiques
Isoxazoles
0
Protein Kinase Inhibitors
0
Pyrazines
0
Pyridines
0
Quinolines
0
Triazoles
0
MTOR protein, human
EC 2.7.1.1
ATM protein, human
EC 2.7.11.1
ATR protein, human
EC 2.7.11.1
Ataxia Telangiectasia Mutated Proteins
EC 2.7.11.1
TOR Serine-Threonine Kinases
EC 2.7.11.1
1-ethyl-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino(2,3-b)pyrazin-2(1H)-one
FII75TFH5L
berzosertib
L423PRV3V3
AZD0156
P5T0XWC07Z
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
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